Innate immune receptors survey the intra- and extracellular environments and are poised to rapidly respond to danger signals. This response consists of inflammatory cytokine production and cell-specific effector mechanisms. Mutations in several intracellular innate immune sensors have previously been associated with innate immune activation not attributable to infection or malignancy: so-called autoinflammatory syndromes. The NOD-like Receptors (NLRs) are a family of proteins sharing a tripartite domain structure, some of which function as intracellular innate immune sensors. Using whole exome sequencing, we identified that a gain-of-function mutation in NLRC4 results in a distinct, severe, early-onset autoinflammatory disease. The phenotype of this mutation involved an early-onset enteropathy that gave way to recurrent fever flares clinically similar to Macrophage Activation Syndrome (MAS). We found that this mutation resulted in spontaneous inflammasome aggregation as measured by fluorescence microscopy. Both patient macrophages and a macrophage cell line transduced to express the mutant protein also showed spontaneous inflammasome activation. The most striking finding was that the NLRC4 mutation resulted in spontaneous IL-18 release, while this was not found in patients with NLRP3 mutations. Finally, we treated this patient with a targeted therapy blocking the actions of IL-1, and noted a dramatic reduction in the patients symptoms, enabling cessation of her immunosuppression. The continuation of this line of research will help uncover the important functions of NLRC4, will allow a greater appreciation for the diversity of inflammasome functions based on molecular and cellular context, and will better define the understudied role of IL-18 in human disease. These discoveries will hopefully lead to the identification of pathways relevant to the pathogenesis of many autoinflammatory and cytokine storm disorders, and new therapeutic targets.